title: Structures of the atlastin GTPase provide insight into homotypic fusion of endoplasmic reticulum membranes.
abstract: The generation of the tubular network of the endoplasmic reticulum (ER) requires homotypic membrane fusion that is mediated by the dynamin-like, membrane-bound GTPase atlastin (ATL). Here, we have determined crystal structures of the cytosolic segment of human ATL1, which give insight into the mechanism of membrane fusion. The structures reveal a GTPase domain and athree-helix bundle, connected by a linker region. One structure corresponds to a prefusion state, in which ATL molecules in apposing membranes interact through their GTPase domains to form a dimer with the nucleotides bound at the interface. The other structure corresponds to a postfusion state generated after GTP hydrolysis and phosphate release. Compared with the prefusion structure, the three-helix bundles of the two ATL molecules undergo a major conformational change relative to the GTPase domains, which could pull the membranes together. The proposed fusion mechanism is supported by biochemical experiments and fusion assays with wild-type and mutant full-length Drosophila ATL. These experiments also show that membrane fusion is facilitated by the C-terminal cytosolic tails following the two transmembrane segments. Finally, our results show that mutations in ATL1 causing hereditary spastic paraplegia compromise homotypic ER fusion.
authors.affiliation: Department of Genetics and Cell Biology, College of Life Sciences, and Tianjin Key Laboratory of Protein Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Bian
authors.forename: Robin W
authors.initials: RW
authors.lastname: Klemm
authors.forename: Tina Y
authors.initials: TY
authors.lastname: Liu
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.forename: Sha
authors.initials: S
authors.lastname: Sun
authors.forename: Xuewu
authors.initials: X
authors.lastname: Sui
authors.forename: Xinqi
authors.initials: X
authors.lastname: Liu
authors.forename: Tom A
authors.initials: TA
authors.lastname: Rapoport
authors.forename: Junjie
authors.initials: J
authors.lastname: Hu
mesh_terms: D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008561:Membrane Fusion; D008565:Membrane Proteins; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation
chemical_list: D008565:Membrane Proteins; D006160:Guanosine Triphosphate; C440006:ATL1 protein, human; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins